高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (6): 1189.doi: 10.7503/cjcu20131048
收稿日期:
2013-10-28
出版日期:
2014-06-10
发布日期:
2014-01-13
作者简介:
联系人简介: 方 浩, 男, 博士, 教授, 博士生导师, 主要从事药物化学中抗肿瘤药物研究. E-mail:基金资助:
WANG Junhua, WANG Quande, DUN Yanyan, FANG Hao*()
Received:
2013-10-28
Online:
2014-06-10
Published:
2014-01-13
Contact:
FANG Hao
E-mail:haofangcn@sdu.edu.cn
Supported by:
摘要:
合成了一系列结构全新的嘌呤磺胺类衍生物, 并应用溴化噻唑蓝四氮唑(MTT)法进行了初步体外抗肿瘤细胞增殖活性研究. 结果表明, 嘌呤环C2位、 N6位和N9位的取代对活性均有较大影响, C2位引入苯磺酰基哌嗪片段后有利于提高抗肿瘤活性. 化合物17d对3株肿瘤细胞PC-3, HCT116和K562 的增殖均有明显抑制作用, 且强度与阳性对照药Roscovitine相近.
中图分类号:
TrendMD:
王军华, 王泉德, 顿艳艳, 方浩. 嘌呤磺胺衍生物的合成及抗肿瘤活性. 高等学校化学学报, 2014, 35(6): 1189.
WANG Junhua, WANG Quande, DUN Yanyan, FANG Hao. Syntheses and Antitumor Activities of Purine-sulfonamides Derivatives†. Chem. J. Chinese Universities, 2014, 35(6): 1189.
Scheme 1 Synthesis routes of target compounds 5a—5c and 8a—8da. Chloromethyl pivalate(Pom-Cl), K2CO3, DMSO, r. t. or 2-bromopropane, K2CO3, DMSO, 80 ℃; b. benzyl amine, TEA, n-butanol, reflux; c. arylsulfonyl chloride, pyridine, r. t.; d. 3 mol/L NaOH, THF, r. t.; e. 4-methoxybenzene sulfonyl chloride, pyridine, r. t.; f. benzyl amine, TEA, n-butanol, reflux.
Scheme 2 Synthesis routes of target compounds 13a—13g and 17a—17ha. Benzyl amine or aminomethylcyclohexane, TEA, n-butanol, reflux; b. 2-bromopropane, K2CO3, DMSO, 80 ℃; c. piperazine, n-butanol, N2, 110 ℃; d. arylsulfonyl chloride, pyridine, r. t..
Scheme 3 Synthesis routes of target compounds 21a—21ca. Ethyl chloroacetate, K2CO3, DMSO, 90 ℃; b. piperazine, n-butanol, N2, 110 ℃; c. arylsulfonyl chloride, pyridine, r. t.; d. 2 mol/L NaOH, THF, r. t.. R: a. 4-F; b. 2,6-difluoro; c. 4-OCH3.
Compd. | m.p./℃ | Yield(%) | Appearance | HRMS(calcd.)[M+H]+ |
---|---|---|---|---|
5a | 254(Dec.) | 77 | White solid | 399.1034(399.1034) |
5b | 258(Dec.) | 65 | White solid | 417.0940(417.0940) |
5c | 286(Dec.) | 82 | White solid | 465.0955(465.0951) |
8a | 241—244 | 32 | Light pink solid | 459.1406(459.1409) |
8b | 215—218 | 24 | White solid | 491.1468(491.1472) |
8c | 245—246 | 60 | Light yellow solid | 468.1444(468.1449) |
8d | 206—208 | 5.5 | White solid | 453.1703(453.1703) |
13a | 86—90 | 39 | Light yellow solid | 506.2329(506.2333) |
13b | 80—83 | 42 | Light yellow solid | 526.1784(526.1786) |
13c | 108—111 | 59 | White solid | 528.1984(528.1988) |
13d | 86—88 | 65 | Gray solid | 560.2050(560.2050) |
13e | 226—228 | 28 | Brick red solid | 537.2023(537.2027) |
13f | 81—84 | 42 | Light yellow solid | 522.2279(522.2282) |
13g | 76—78 | 38 | Light yellow solid | 576.2000(576.1999) |
17a | 146—150 | 11 | White solid | 512.2803(512.2802) |
17b | 157—160 | 19 | White solid | 532.2254(532.2256) |
17c | 119—121 | 16 | White solid | 516.2548(516.2552) |
17d | 186—190 | 42 | White solid | 534.2454(534.2457) |
17e | 192—194 | 67 | White solid | 566.2520(566.2520) |
17f | 198—200 | 48 | Yellow solid | 543.2494(543.2496) |
17g | 148—150 | 15 | White solid | 528.2748(528.2751) |
17h | 167—168 | 59 | White solid | 582.2468(582.2469) |
21a | 256(Dec.) | 78 | White solid | 532.2130(532.2137) |
21b | 275(Dec.) | 47 | White solid | 550.2044(550.2043) |
21c | 228(Dec.) | 91 | White solid | 544.2326(544.2337) |
Table 1 Physical data and HRMS results of all target compounds
Compd. | m.p./℃ | Yield(%) | Appearance | HRMS(calcd.)[M+H]+ |
---|---|---|---|---|
5a | 254(Dec.) | 77 | White solid | 399.1034(399.1034) |
5b | 258(Dec.) | 65 | White solid | 417.0940(417.0940) |
5c | 286(Dec.) | 82 | White solid | 465.0955(465.0951) |
8a | 241—244 | 32 | Light pink solid | 459.1406(459.1409) |
8b | 215—218 | 24 | White solid | 491.1468(491.1472) |
8c | 245—246 | 60 | Light yellow solid | 468.1444(468.1449) |
8d | 206—208 | 5.5 | White solid | 453.1703(453.1703) |
13a | 86—90 | 39 | Light yellow solid | 506.2329(506.2333) |
13b | 80—83 | 42 | Light yellow solid | 526.1784(526.1786) |
13c | 108—111 | 59 | White solid | 528.1984(528.1988) |
13d | 86—88 | 65 | Gray solid | 560.2050(560.2050) |
13e | 226—228 | 28 | Brick red solid | 537.2023(537.2027) |
13f | 81—84 | 42 | Light yellow solid | 522.2279(522.2282) |
13g | 76—78 | 38 | Light yellow solid | 576.2000(576.1999) |
17a | 146—150 | 11 | White solid | 512.2803(512.2802) |
17b | 157—160 | 19 | White solid | 532.2254(532.2256) |
17c | 119—121 | 16 | White solid | 516.2548(516.2552) |
17d | 186—190 | 42 | White solid | 534.2454(534.2457) |
17e | 192—194 | 67 | White solid | 566.2520(566.2520) |
17f | 198—200 | 48 | Yellow solid | 543.2494(543.2496) |
17g | 148—150 | 15 | White solid | 528.2748(528.2751) |
17h | 167—168 | 59 | White solid | 582.2468(582.2469) |
21a | 256(Dec.) | 78 | White solid | 532.2130(532.2137) |
21b | 275(Dec.) | 47 | White solid | 550.2044(550.2043) |
21c | 228(Dec.) | 91 | White solid | 544.2326(544.2337) |
Compd. | 1H NMR, δa,b,c | 13C NMR, δd,e | |
---|---|---|---|
5aa,d | 4.53(br s, 2H, CH2), 7.15—7.18(m, 2H, ArH), 7.25—7.30(m, 5H, ArH), 7.90—7.95(m, 3H, ArH, purine C8), 8.25(br s, 1H, NH), 11.08(br s, 1H, SO2NH), 12.76(br s, 1H, purine C9) | 163.78(d,J=249 Hz), 153.33, 152.43, 150.55, 139.54, 138.64, 138.21, 129.80(d, J=5.25 Hz), 128.15, 127.34, 126.71, 115.60(d, J=22.5 Hz), 42.80 | |
5ba,d | 4.38(br s, 2H, CH2), 6.98—7.08(m, 2H, ArH), 7.20—7.27(m, 5H, ArH), 7.41—7.48(m, 1H, ArH), 7.99(s, 1H, purine C8), 8.32(br s, 1H, NH), 11.72(br s, 1H, SO2NH), 12.84(br s, 1H, purine C9) | 158.72(dd,J=4.5, 252.75 Hz), 153.14, 152.40, 149.49, 139.67, 138.64, 133.34, 128.25, 127.68, 126.98, 112,72(d, J=24 Hz), 42.76 | |
5ca,d | 4.49(br s, 2H, CH2), 7.25—7.31(m, 7H, ArH), 7.89—7.99(m, 3H, ArH, purine C8), 8.35(br s, 1H, NH) | 153.00, 152.84, 150.13, 141.68, 139.29, 129.19, 128.15, 127.32, 126.72, 120.54, 119.80(q, J=256.5 Hz), 111.54, 42.84 | |
8ab,d | 1.36[d, J=6.3 Hz, 6H, (CH3)2], 4.47—4.53(m, 3H, CH, CH2), 7.16(t, J=9.0 Hz, 2H, ArH), 7.20—7.29(m, 5H, ArH), 7.54—7.64(m, 1H, ArH), 8.21(s, 1H, purine C8), 8.46(br s, 1H, NH), 11.74(br s, 1H, SO2NH) | 158.87(d,J=255 Hz), 153.30, 152.63, 148.26, 139.12, 137.45, 134.91, 128.17, 127.52, 126.81, 118.94, 113.06(d, J=24 Hz), 113.05(t, J=11.25 Hz), 47.33, 42.73, 21.56 | |
8b b,d | 1.37[d, J=6.6 Hz, 6H, (CH3)2], 4.48—4.54(m, 3H, CH, CH2), 7.18—7.28(m, 5H, ArH), 7.81(d, J=7.2 Hz, 2H, ArH), 8.05(s, 1H, purine C8), 8.10(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.39(br s, 1H, SO2NH) | 154.12, 151.77, 148.66, 145.29, 139.66, 137.74, 131.94(q, J=31.5 Hz), 128.11, 128.01, 127.25, 126.64, 125.92, 123.43(q, J=271.5 Hz), 115.53, 46.58, 42.71, 21.73 | |
8cb,d | 1.41[d, J=6.3 Hz, 6H, (CH3)2], 4.50—4.52(m, 3H, CH, CH2), 7.16—7.22(m, 5H, ArH), 8.05(s, 1H, purine C8), 8.09(d, J=7.2 Hz, 2H, ArH), 8.18(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.49(br s, 1H, SO2NH) | 154.14, 151.62, 149.08, 147.06, 139.51, 137.71, 128.29, 127.95, 126.93, 126.48, 123.97, 115.78, 46.39, 42.59, 21.85 | |
8d c,d | 1.51[d, J=6.6 Hz, 6H, (CH3)2], 3.80(s, 3H, OCH3), 4.63(hept, J=6.6 Hz, 1H, CH), 4.72(br s, 2H, CH2), 6.52(br s, 1H, NH), 6.81(d, J=9.0 Hz, 2H, ArH), 7.26—7.32(m, 5H, ArH), 7.61(s, 1H, purine C8), 8.01(d, J=9.0 Hz, 2H, ArH), 8.24(br s, 1H, SO2NH) | 162.03, 154.29, 151.94, 149.12, 139.94, 137.41, 132.69, 129.44, 128.01, 127.37, 126.50, 115.84, 113.61, 59.64, 46.24, 42.58, 21.88 | |
Compd. | 1H NMR, δa,b,c | 13C NMR, δd,e | |
13a a,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.37(s, 3H, CH3), 2.75—2.78(m, 4H, piperazine), 3.74—3.82(m, 4H, piperazine), 4.50—4.52(m, 3H, CH, CH2), 7.22—7.32(m, 5H, ArH), 7.42(d, J=7.8 Hz, 2H, ArH), 7.58(d, J=7.8 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.11(br s, 1H, NH) | 158.80, 152.94, 150.20, 143.77, 139.13, 133.86, 132.47, 129.70, 128.31, 127.82, 127.61, 126.91, 109.51, 47.47, 45.85, 44.42, 43.72, 22.12, 21.04 | |
13b a,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.81—2.88(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.50—4.55(m, 3H, CH, CH2), 7.21—7.32(m, 5H, ArH), 7.70(d, J=8.4 Hz, 2H, ArH), 7.72(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.09(br s, 1H, NH) | 158.74, 153.35, 150.50, 139.53, 139.08, 134.13, 133.89, 129.41, 129.15, 128.40, 127.60, 127.04, 111.01, 47.11, 45.79, 44.50, 43.77, 22.30 | |
13c a,d | 1.43[d, J=6.6 Hz, 6H, (CH3)2], 2.99—3.13(m, 4H, piperazine), 3.76—3.85(m, 4H, piperazine), 4.49—4.57(m, 3H, CH, CH2), 7.18—7.35(m, 7H, ArH), 7.75—7.77(m, 1H, ArH), 7.87(s, 1H, purine C8), 8.11(br s, 1H, NH) | 158.80(dd,J=3.75, 255 Hz), 157.34, 153.92, 150.21, 140.52, 136.21(t, J=11.25 Hz), 135.99, 127.90, 127.35, 126.37, 113.68(dd, J=3, 23.25 Hz), 113.35, 113.13, 45.67, 44.86, 43.40, 42.62, 21.97 | |
13d a,d | 1.43[d, J=6.6 Hz, 6H, (CH3)2], 2.79—3.03(m, 4H, piperazine), 3.71—3.89(m, 4H, piperazine), 4.45—4.61(m, 3H, CH, CH2), 7.19—7.32(m, 5H, ArH), 7.90(s, 1H, purine C8), 7.94(d, J=7.8 Hz, 2H, ArH), 8.02(d, J=7.8 Hz, 2H, ArH), 8.10(br s, 1H, NH) | 157.31, 153.85, 150.20, 140.50, 138.88, 135.99, 132.82(q, J=32.25 Hz), 128.47, 127.99, 127.37, 126.59(q, J=3.75 Hz), 126.40, 123.35(q, J=271.5 Hz), 113.45, 45.77, 45.45, 43.24, 42.65, 21.97 | |
13ea,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.87—2.93(m, 4H, piperazine), 3.76—3.80(m, 4H, piperazine), 4.48—4.55(m, 3H, CH, CH2), 7.21—7.31(m, 5H, ArH), 7.85(s, 1H, purine C8), 7.98(d, J=8.4 Hz, 2H, ArH), 8.10(br s, 1H, NH), 8.41(d, J=8.4 Hz, 2H, ArH) | 158.04, 154.34, 150.87, 150.22, 141.82, 139.21, 135.16, 128.89, 128.51, 127.51, 127.18, 124.31, 114.23, 46.42, 45.79, 44.45, 43.86, 22.48 | |
13f a,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.75—2.78(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.49—4.52(m, 3H, CH, CH2), 7.13(d, J=8.4 Hz, 2H, ArH), 7.21—7.33(m, 5H, ArH), 7.64(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.12(br s, 1H, NH) | 163.11, 158.73, 153.25, 150.31, 139.27, 133.92, 129.90, 128.30, 127.62, 127.02, 126.87, 114.24, 110.44, 55.62, 47.16, 45.87, 44.38, 43.72, 22.21 | |
13g a,e | 1.42[d,J=6.6 Hz, 6H, (CH3)2], 2.84—2.90(m, 4H, piperazine), 3.76—3.81(m, 4H, piperazine), 4.50—4.56(m, 3H, CH, CH2), 7.19—7.32(m, 5H, ArH), 7.62(d, J=8.4 Hz, 2H, ArH), 7.86—7.88(m, 3H, purine C8, ArH), 8.10(br s, 1H, NH) | 158.68, 153.30, 152.36, 150.30, 139.24, 134.04, 133.96, 129.88, 128.31, 127.59, 126.90, 120.89, 120.19(q, J=258 Hz), 110.60, 47.19, 45.81, 44.40, 43.72, 22.22 | |
17ac,e | 0.96—1.01(m, 2H, cyclohexyl), 1.14—1.25(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH3)2], 1.57—1.79(m, 6H, cyclohexyl), 2.41(s, 3H, CH3), 3.04—3.06(m, 4H, piperazine CH2), 3.35(br s, 2H, CH2), 3.90—3.92(m, 4H, piperazine CH2), 4.62(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.30(d, J=8.4 Hz, 2H, ArH), 7.53(s, 1H, purine C8), 7.65(d, J=8.4 Hz, 2H, ArH) | 158.30, 154.72, 150.65, 143.67, 134.70, 132.53, 129.65, 127.87, 114.02, 46.65, 46.33, 46.02, 43.85, 38.34, 31.00, 26.45, 25.94, 22.50, 21.50 | |
17b a,e | 0.88—0.90(m, 2H, cyclohexyl), 1.07—1.15(m, 3H, cyclohexyl), 1.46[d, J=6.6 Hz, 6H, (CH3)2], 1.57—1.68(m, 6H, cyclohexyl), 2.92—2.98(m, 4H, piperazine), 3.24(br s, 2H, CH2), 3.78—3.88(m, 4H, piperazine), 4.57(hept, J=6.6 Hz, 1H, CH), 7.45(br s, 1H, NH), 7.71(d, J=8.4 Hz, 2H, ArH), 7.76(d, J=8.4 Hz, 2H, ArH), 7.87(s, 1H, purine C8) | 158.22, 154.82, 150.63, 139.47, 134.81, 134.21, 129.37, 129.19, 114.25, 46.68, 46.33, 45.95, 43.84, 38.35, 31.01, 26.45, 25.94, 22.51 | |
17c a,e | 0.88—0.92(m, 2H, cyclohexyl), 1.12—1.19(m, 3H, cyclohexyl), 1.44[d, J=6.6 Hz, 6H, (CH3)2], 1.59—1.67(m, 6H, cyclohexyl), 2.91—2.97(m, 4H, piperazine), 3.22(br s, 2H, CH2), 3.77—3.83(m, 4H, piperazine), 4.54(hept, J=6.6 Hz, 1H, CH), 7.44—7.48(m, 3H, NH, ArH), 7.81—7.84(m, 3H, ArH, purine C8) | 165.28(d, J=253.5 Hz), 158.18, 154.74, 134.75, 131.82(d, J=3 Hz), 130.47(d, J=9 Hz), 116.33(d, J=22.5 Hz), 114.07, 46.65, 46.39, 45.97, 43.88, 38.36, 31.02, 26.46, 25.95, 22.50 | |
17dc,e | 0.97—1.03(m, 2H, cyclohexyl), 1.15—1.22(m, 3H, cyclohexyl), 1.54[d, J=6.6 Hz, 6H, (CH3)2], 1.62—1.81(m, 6H, cyclohexyl), 3.29—3.34(m, 4H, piperazine), 3.37(br s, 2H, CH2), 3.93—4.02(m, 4H, piperazine), 4.66(hept, J=6.6 Hz, 1H, CH), 6.22(br s, 1H, NH), 7.04(t, J=9.0 Hz, 2H, ArH), 7.50—7.54(m, 1H, ArH), 7.62(s, 1H, purine C8) | 159.88(dd,J=3.75, 258 Hz), 154.25, 152.36, 150.53, 134.68(t, J=11.25 Hz), 115.05(t, J=16.5 Hz), 113.23(dd, J=3.75, 24 Hz), 112.54, 47.76, 46.80, 45.54, 44.09, 38.22, 31.01, 26.43, 25.92, 22.42 | |
Compd. | 1H NMR, δa,b,c | 13C NMR, δd,e | |
17ec,e | 0.97—1.01(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.51[d,J=6.6 Hz, 6H,(CH3)2], 1.57—1.79(m, 6H, cyclohexyl), 3.08—3.14(m, 4H, piperazine), 3.35(br s, 2H, CH2), 3.92—3.96(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.66(br s, 1H, NH), 7.52(s, 1H, purine C8), 7.79(d, J=8.4 Hz, 2H, ArH), 7.90(d, J=8.4 Hz, 2H, ArH) | 158.19, 154.88, 150.69, 139.47, 134.88, 134.57(q, J=33 Hz), 128.27, 126.22(q, J=3.75 Hz), 123.20(q, J=271.5 Hz), 114.35, 46.71, 46.33, 45.98, 43.85, 38.35, 31.02, 26.45, 25.95, 22.51 | |
17f c,e | 0.94—0.99(m, 2H, cyclohexyl), 1.14—1.26(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH3)2], 1.53—1.77(m, 6H, cyclohexyl), 3.11—3.13(m, 4H, piperazine), 3.34(br s, 2H, CH2), 3.93—3.97(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.90(br s, 1H, NH), 7.51(s, 1H, purine C8), 7.95(d, J=9.0 Hz, 2H, ArH), 8.35(d, J=9.0 Hz, 2H, ArH) | 158.11, 154.88, 150.60, 150.22, 141.87, 134.92, 128.91, 124.31, 114.38, 46.71, 46.33, 45.89, 43.87, 38.34, 31.00, 26.44, 25.94, 22.50 | |
17g c,e | 0.96—1.02(m, 2H, cyclohexyl), 1.16—1.22(m, 3H, cyclohexyl), 1.52[d, J=6.6 Hz, 6H, (CH3)2], 1.67—1.80(m, 6H, cyclohexyl), 3.01—3.11(m, 4H, piperazine), 3.37(br s, 2H, CH2), 3.87(s, 3H, OCH3), 3.88—3.99(m, 4H, piperazine), 4.63(hept, J=6.6 Hz, 1H, CH), 5.72(br s, 1H, NH), 6.99(d, J=7.8 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.72(d, J=7.8 Hz, 2H, ArH) | 163.07, 158.31, 154.80, 150.67, 134.75, 129.93, 127.15, 114.20, 55.59, 46.74, 46.29, 46.02, 43.84, 38.35, 31.00, 26.46, 25.95, 22.51 | |
17h c,e | 0.95—1.01(m, 2H, cyclohexyl), 1.14—1.24(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH3)2], 1.55—1.78(m, 6H, cyclohexyl), 3.07—3.13(m, 4H, piperazine), 3.35(br s, 2H, CH2), 3.91—3.95(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.34(d, J=8.4 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.82(d, J=8.4 Hz, 2H, ArH) | 158.18, 154.81, 150.67, 139.45, 134.83, 134.14(q, J=33 Hz), 128.26, 126.22(q, J=3.75 Hz), 123.19(q, J=271.5 Hz), 114.25, 46.70, 46.35, 45.97, 43.85, 38.34, 31.01, 26.45, 25.94, 22.51 | |
21a a,d | 0.87—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.70(m, 6H, cyclohexyl), 2.85—3.05(m, 4H, piperazine), 3.24(br s, 2H, CH2), 3.70—3.89(m, 4H, piperazine), 4.77(s, 2H, CH2), 7.46—7.49(m, 3H, ArH, NH), 7.75(s, 1H, purine C8), 7.83(dd, J=7.2, 5.4 Hz, 2H, ArH), 13.12(br s, 1H, COOH) | 169.49, 164.64(d, J=250.5 Hz), 157.83, 154.44, 150.71, 138.31, 131.23, 130.58(d, J=9.75 Hz), 116.59(d, J=22.5 Hz), 112.66, 45.79, 45.63, 43.35, 43.18, 37.57, 30.53, 26.08, 25.45 | |
21ba,d | 0.85—0.98(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.71(m, 6H, cyclohexyl), 3.11—3.20(m, 4H, piperazine), 3.25(br s, 2H, CH2), 3.74—3.94(m, 4H, piperazine), 4.79(s, 2H, CH2), 7.33(t, J=9.0 Hz, 2H, ArH), 7.50(br s, 1H, NH), 7.70—7.86(m, 2H, ArH, purine C8), 13.12(br s, 1H, COOH) | 169.51, 158.92(dd, J=3.75, 255 Hz), 157.87, 154.48, 150.78, 138.34, 136.26(t, J=10.5 Hz), 113.71(dd, J=3, 24 Hz), 113.33, 112.77, 45.81, 45.00, 43.44, 43.35, 37.62, 30.54, 26.08, 25.46 | |
21ca,d | 0.86—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.61—1.67(m, 6H, cyclohexyl), 2.78—2.96(m, 4H, piperazine), 3.23(br s, 2H, CH2), 3.72—3.81(m, 4H, piperazine), 3.83(s, 3H, OCH3), 4.76(s, 2H, CH2), 7.13(d, J=7.8 Hz, 2H, ArH), 7.47(br s, 1H, NH), 7.68(d, J=7.8 Hz, 2H, ArH), 7.73(s, 1H, purine C8), 13.06(br s, 1H, COOH) | 169.50, 162.77, 157.79, 154.48, 150.83, 138.29, 129.74, 126.18, 114.50, 112.76, 55.62, 45.75, 45.61, 43.34, 43.21, 37.56, 30.54, 26.09, 25.47 |
Table 2 Spectral date of all target compounds*
Compd. | 1H NMR, δa,b,c | 13C NMR, δd,e | |
---|---|---|---|
5aa,d | 4.53(br s, 2H, CH2), 7.15—7.18(m, 2H, ArH), 7.25—7.30(m, 5H, ArH), 7.90—7.95(m, 3H, ArH, purine C8), 8.25(br s, 1H, NH), 11.08(br s, 1H, SO2NH), 12.76(br s, 1H, purine C9) | 163.78(d,J=249 Hz), 153.33, 152.43, 150.55, 139.54, 138.64, 138.21, 129.80(d, J=5.25 Hz), 128.15, 127.34, 126.71, 115.60(d, J=22.5 Hz), 42.80 | |
5ba,d | 4.38(br s, 2H, CH2), 6.98—7.08(m, 2H, ArH), 7.20—7.27(m, 5H, ArH), 7.41—7.48(m, 1H, ArH), 7.99(s, 1H, purine C8), 8.32(br s, 1H, NH), 11.72(br s, 1H, SO2NH), 12.84(br s, 1H, purine C9) | 158.72(dd,J=4.5, 252.75 Hz), 153.14, 152.40, 149.49, 139.67, 138.64, 133.34, 128.25, 127.68, 126.98, 112,72(d, J=24 Hz), 42.76 | |
5ca,d | 4.49(br s, 2H, CH2), 7.25—7.31(m, 7H, ArH), 7.89—7.99(m, 3H, ArH, purine C8), 8.35(br s, 1H, NH) | 153.00, 152.84, 150.13, 141.68, 139.29, 129.19, 128.15, 127.32, 126.72, 120.54, 119.80(q, J=256.5 Hz), 111.54, 42.84 | |
8ab,d | 1.36[d, J=6.3 Hz, 6H, (CH3)2], 4.47—4.53(m, 3H, CH, CH2), 7.16(t, J=9.0 Hz, 2H, ArH), 7.20—7.29(m, 5H, ArH), 7.54—7.64(m, 1H, ArH), 8.21(s, 1H, purine C8), 8.46(br s, 1H, NH), 11.74(br s, 1H, SO2NH) | 158.87(d,J=255 Hz), 153.30, 152.63, 148.26, 139.12, 137.45, 134.91, 128.17, 127.52, 126.81, 118.94, 113.06(d, J=24 Hz), 113.05(t, J=11.25 Hz), 47.33, 42.73, 21.56 | |
8b b,d | 1.37[d, J=6.6 Hz, 6H, (CH3)2], 4.48—4.54(m, 3H, CH, CH2), 7.18—7.28(m, 5H, ArH), 7.81(d, J=7.2 Hz, 2H, ArH), 8.05(s, 1H, purine C8), 8.10(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.39(br s, 1H, SO2NH) | 154.12, 151.77, 148.66, 145.29, 139.66, 137.74, 131.94(q, J=31.5 Hz), 128.11, 128.01, 127.25, 126.64, 125.92, 123.43(q, J=271.5 Hz), 115.53, 46.58, 42.71, 21.73 | |
8cb,d | 1.41[d, J=6.3 Hz, 6H, (CH3)2], 4.50—4.52(m, 3H, CH, CH2), 7.16—7.22(m, 5H, ArH), 8.05(s, 1H, purine C8), 8.09(d, J=7.2 Hz, 2H, ArH), 8.18(d, J=7.2 Hz, 2H, ArH), 8.36(br s, 1H, NH), 11.49(br s, 1H, SO2NH) | 154.14, 151.62, 149.08, 147.06, 139.51, 137.71, 128.29, 127.95, 126.93, 126.48, 123.97, 115.78, 46.39, 42.59, 21.85 | |
8d c,d | 1.51[d, J=6.6 Hz, 6H, (CH3)2], 3.80(s, 3H, OCH3), 4.63(hept, J=6.6 Hz, 1H, CH), 4.72(br s, 2H, CH2), 6.52(br s, 1H, NH), 6.81(d, J=9.0 Hz, 2H, ArH), 7.26—7.32(m, 5H, ArH), 7.61(s, 1H, purine C8), 8.01(d, J=9.0 Hz, 2H, ArH), 8.24(br s, 1H, SO2NH) | 162.03, 154.29, 151.94, 149.12, 139.94, 137.41, 132.69, 129.44, 128.01, 127.37, 126.50, 115.84, 113.61, 59.64, 46.24, 42.58, 21.88 | |
Compd. | 1H NMR, δa,b,c | 13C NMR, δd,e | |
13a a,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.37(s, 3H, CH3), 2.75—2.78(m, 4H, piperazine), 3.74—3.82(m, 4H, piperazine), 4.50—4.52(m, 3H, CH, CH2), 7.22—7.32(m, 5H, ArH), 7.42(d, J=7.8 Hz, 2H, ArH), 7.58(d, J=7.8 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.11(br s, 1H, NH) | 158.80, 152.94, 150.20, 143.77, 139.13, 133.86, 132.47, 129.70, 128.31, 127.82, 127.61, 126.91, 109.51, 47.47, 45.85, 44.42, 43.72, 22.12, 21.04 | |
13b a,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.81—2.88(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.50—4.55(m, 3H, CH, CH2), 7.21—7.32(m, 5H, ArH), 7.70(d, J=8.4 Hz, 2H, ArH), 7.72(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.09(br s, 1H, NH) | 158.74, 153.35, 150.50, 139.53, 139.08, 134.13, 133.89, 129.41, 129.15, 128.40, 127.60, 127.04, 111.01, 47.11, 45.79, 44.50, 43.77, 22.30 | |
13c a,d | 1.43[d, J=6.6 Hz, 6H, (CH3)2], 2.99—3.13(m, 4H, piperazine), 3.76—3.85(m, 4H, piperazine), 4.49—4.57(m, 3H, CH, CH2), 7.18—7.35(m, 7H, ArH), 7.75—7.77(m, 1H, ArH), 7.87(s, 1H, purine C8), 8.11(br s, 1H, NH) | 158.80(dd,J=3.75, 255 Hz), 157.34, 153.92, 150.21, 140.52, 136.21(t, J=11.25 Hz), 135.99, 127.90, 127.35, 126.37, 113.68(dd, J=3, 23.25 Hz), 113.35, 113.13, 45.67, 44.86, 43.40, 42.62, 21.97 | |
13d a,d | 1.43[d, J=6.6 Hz, 6H, (CH3)2], 2.79—3.03(m, 4H, piperazine), 3.71—3.89(m, 4H, piperazine), 4.45—4.61(m, 3H, CH, CH2), 7.19—7.32(m, 5H, ArH), 7.90(s, 1H, purine C8), 7.94(d, J=7.8 Hz, 2H, ArH), 8.02(d, J=7.8 Hz, 2H, ArH), 8.10(br s, 1H, NH) | 157.31, 153.85, 150.20, 140.50, 138.88, 135.99, 132.82(q, J=32.25 Hz), 128.47, 127.99, 127.37, 126.59(q, J=3.75 Hz), 126.40, 123.35(q, J=271.5 Hz), 113.45, 45.77, 45.45, 43.24, 42.65, 21.97 | |
13ea,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.87—2.93(m, 4H, piperazine), 3.76—3.80(m, 4H, piperazine), 4.48—4.55(m, 3H, CH, CH2), 7.21—7.31(m, 5H, ArH), 7.85(s, 1H, purine C8), 7.98(d, J=8.4 Hz, 2H, ArH), 8.10(br s, 1H, NH), 8.41(d, J=8.4 Hz, 2H, ArH) | 158.04, 154.34, 150.87, 150.22, 141.82, 139.21, 135.16, 128.89, 128.51, 127.51, 127.18, 124.31, 114.23, 46.42, 45.79, 44.45, 43.86, 22.48 | |
13f a,e | 1.42[d, J=6.6 Hz, 6H, (CH3)2], 2.75—2.78(m, 4H, piperazine), 3.75—3.80(m, 4H, piperazine), 4.49—4.52(m, 3H, CH, CH2), 7.13(d, J=8.4 Hz, 2H, ArH), 7.21—7.33(m, 5H, ArH), 7.64(d, J=8.4 Hz, 2H, ArH), 7.86(s, 1H, purine C8), 8.12(br s, 1H, NH) | 163.11, 158.73, 153.25, 150.31, 139.27, 133.92, 129.90, 128.30, 127.62, 127.02, 126.87, 114.24, 110.44, 55.62, 47.16, 45.87, 44.38, 43.72, 22.21 | |
13g a,e | 1.42[d,J=6.6 Hz, 6H, (CH3)2], 2.84—2.90(m, 4H, piperazine), 3.76—3.81(m, 4H, piperazine), 4.50—4.56(m, 3H, CH, CH2), 7.19—7.32(m, 5H, ArH), 7.62(d, J=8.4 Hz, 2H, ArH), 7.86—7.88(m, 3H, purine C8, ArH), 8.10(br s, 1H, NH) | 158.68, 153.30, 152.36, 150.30, 139.24, 134.04, 133.96, 129.88, 128.31, 127.59, 126.90, 120.89, 120.19(q, J=258 Hz), 110.60, 47.19, 45.81, 44.40, 43.72, 22.22 | |
17ac,e | 0.96—1.01(m, 2H, cyclohexyl), 1.14—1.25(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH3)2], 1.57—1.79(m, 6H, cyclohexyl), 2.41(s, 3H, CH3), 3.04—3.06(m, 4H, piperazine CH2), 3.35(br s, 2H, CH2), 3.90—3.92(m, 4H, piperazine CH2), 4.62(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.30(d, J=8.4 Hz, 2H, ArH), 7.53(s, 1H, purine C8), 7.65(d, J=8.4 Hz, 2H, ArH) | 158.30, 154.72, 150.65, 143.67, 134.70, 132.53, 129.65, 127.87, 114.02, 46.65, 46.33, 46.02, 43.85, 38.34, 31.00, 26.45, 25.94, 22.50, 21.50 | |
17b a,e | 0.88—0.90(m, 2H, cyclohexyl), 1.07—1.15(m, 3H, cyclohexyl), 1.46[d, J=6.6 Hz, 6H, (CH3)2], 1.57—1.68(m, 6H, cyclohexyl), 2.92—2.98(m, 4H, piperazine), 3.24(br s, 2H, CH2), 3.78—3.88(m, 4H, piperazine), 4.57(hept, J=6.6 Hz, 1H, CH), 7.45(br s, 1H, NH), 7.71(d, J=8.4 Hz, 2H, ArH), 7.76(d, J=8.4 Hz, 2H, ArH), 7.87(s, 1H, purine C8) | 158.22, 154.82, 150.63, 139.47, 134.81, 134.21, 129.37, 129.19, 114.25, 46.68, 46.33, 45.95, 43.84, 38.35, 31.01, 26.45, 25.94, 22.51 | |
17c a,e | 0.88—0.92(m, 2H, cyclohexyl), 1.12—1.19(m, 3H, cyclohexyl), 1.44[d, J=6.6 Hz, 6H, (CH3)2], 1.59—1.67(m, 6H, cyclohexyl), 2.91—2.97(m, 4H, piperazine), 3.22(br s, 2H, CH2), 3.77—3.83(m, 4H, piperazine), 4.54(hept, J=6.6 Hz, 1H, CH), 7.44—7.48(m, 3H, NH, ArH), 7.81—7.84(m, 3H, ArH, purine C8) | 165.28(d, J=253.5 Hz), 158.18, 154.74, 134.75, 131.82(d, J=3 Hz), 130.47(d, J=9 Hz), 116.33(d, J=22.5 Hz), 114.07, 46.65, 46.39, 45.97, 43.88, 38.36, 31.02, 26.46, 25.95, 22.50 | |
17dc,e | 0.97—1.03(m, 2H, cyclohexyl), 1.15—1.22(m, 3H, cyclohexyl), 1.54[d, J=6.6 Hz, 6H, (CH3)2], 1.62—1.81(m, 6H, cyclohexyl), 3.29—3.34(m, 4H, piperazine), 3.37(br s, 2H, CH2), 3.93—4.02(m, 4H, piperazine), 4.66(hept, J=6.6 Hz, 1H, CH), 6.22(br s, 1H, NH), 7.04(t, J=9.0 Hz, 2H, ArH), 7.50—7.54(m, 1H, ArH), 7.62(s, 1H, purine C8) | 159.88(dd,J=3.75, 258 Hz), 154.25, 152.36, 150.53, 134.68(t, J=11.25 Hz), 115.05(t, J=16.5 Hz), 113.23(dd, J=3.75, 24 Hz), 112.54, 47.76, 46.80, 45.54, 44.09, 38.22, 31.01, 26.43, 25.92, 22.42 | |
Compd. | 1H NMR, δa,b,c | 13C NMR, δd,e | |
17ec,e | 0.97—1.01(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.51[d,J=6.6 Hz, 6H,(CH3)2], 1.57—1.79(m, 6H, cyclohexyl), 3.08—3.14(m, 4H, piperazine), 3.35(br s, 2H, CH2), 3.92—3.96(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.66(br s, 1H, NH), 7.52(s, 1H, purine C8), 7.79(d, J=8.4 Hz, 2H, ArH), 7.90(d, J=8.4 Hz, 2H, ArH) | 158.19, 154.88, 150.69, 139.47, 134.88, 134.57(q, J=33 Hz), 128.27, 126.22(q, J=3.75 Hz), 123.20(q, J=271.5 Hz), 114.35, 46.71, 46.33, 45.98, 43.85, 38.35, 31.02, 26.45, 25.95, 22.51 | |
17f c,e | 0.94—0.99(m, 2H, cyclohexyl), 1.14—1.26(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH3)2], 1.53—1.77(m, 6H, cyclohexyl), 3.11—3.13(m, 4H, piperazine), 3.34(br s, 2H, CH2), 3.93—3.97(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.90(br s, 1H, NH), 7.51(s, 1H, purine C8), 7.95(d, J=9.0 Hz, 2H, ArH), 8.35(d, J=9.0 Hz, 2H, ArH) | 158.11, 154.88, 150.60, 150.22, 141.87, 134.92, 128.91, 124.31, 114.38, 46.71, 46.33, 45.89, 43.87, 38.34, 31.00, 26.44, 25.94, 22.50 | |
17g c,e | 0.96—1.02(m, 2H, cyclohexyl), 1.16—1.22(m, 3H, cyclohexyl), 1.52[d, J=6.6 Hz, 6H, (CH3)2], 1.67—1.80(m, 6H, cyclohexyl), 3.01—3.11(m, 4H, piperazine), 3.37(br s, 2H, CH2), 3.87(s, 3H, OCH3), 3.88—3.99(m, 4H, piperazine), 4.63(hept, J=6.6 Hz, 1H, CH), 5.72(br s, 1H, NH), 6.99(d, J=7.8 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.72(d, J=7.8 Hz, 2H, ArH) | 163.07, 158.31, 154.80, 150.67, 134.75, 129.93, 127.15, 114.20, 55.59, 46.74, 46.29, 46.02, 43.84, 38.35, 31.00, 26.46, 25.95, 22.51 | |
17h c,e | 0.95—1.01(m, 2H, cyclohexyl), 1.14—1.24(m, 3H, cyclohexyl), 1.51[d, J=6.6 Hz, 6H, (CH3)2], 1.55—1.78(m, 6H, cyclohexyl), 3.07—3.13(m, 4H, piperazine), 3.35(br s, 2H, CH2), 3.91—3.95(m, 4H, piperazine), 4.61(hept, J=6.6 Hz, 1H, CH), 5.68(br s, 1H, NH), 7.34(d, J=8.4 Hz, 2H, ArH), 7.51(s, 1H, purine C8), 7.82(d, J=8.4 Hz, 2H, ArH) | 158.18, 154.81, 150.67, 139.45, 134.83, 134.14(q, J=33 Hz), 128.26, 126.22(q, J=3.75 Hz), 123.19(q, J=271.5 Hz), 114.25, 46.70, 46.35, 45.97, 43.85, 38.34, 31.01, 26.45, 25.94, 22.51 | |
21a a,d | 0.87—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.70(m, 6H, cyclohexyl), 2.85—3.05(m, 4H, piperazine), 3.24(br s, 2H, CH2), 3.70—3.89(m, 4H, piperazine), 4.77(s, 2H, CH2), 7.46—7.49(m, 3H, ArH, NH), 7.75(s, 1H, purine C8), 7.83(dd, J=7.2, 5.4 Hz, 2H, ArH), 13.12(br s, 1H, COOH) | 169.49, 164.64(d, J=250.5 Hz), 157.83, 154.44, 150.71, 138.31, 131.23, 130.58(d, J=9.75 Hz), 116.59(d, J=22.5 Hz), 112.66, 45.79, 45.63, 43.35, 43.18, 37.57, 30.53, 26.08, 25.45 | |
21ba,d | 0.85—0.98(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.62—1.71(m, 6H, cyclohexyl), 3.11—3.20(m, 4H, piperazine), 3.25(br s, 2H, CH2), 3.74—3.94(m, 4H, piperazine), 4.79(s, 2H, CH2), 7.33(t, J=9.0 Hz, 2H, ArH), 7.50(br s, 1H, NH), 7.70—7.86(m, 2H, ArH, purine C8), 13.12(br s, 1H, COOH) | 169.51, 158.92(dd, J=3.75, 255 Hz), 157.87, 154.48, 150.78, 138.34, 136.26(t, J=10.5 Hz), 113.71(dd, J=3, 24 Hz), 113.33, 112.77, 45.81, 45.00, 43.44, 43.35, 37.62, 30.54, 26.08, 25.46 | |
21ca,d | 0.86—0.94(m, 2H, cyclohexyl), 1.15—1.25(m, 3H, cyclohexyl), 1.61—1.67(m, 6H, cyclohexyl), 2.78—2.96(m, 4H, piperazine), 3.23(br s, 2H, CH2), 3.72—3.81(m, 4H, piperazine), 3.83(s, 3H, OCH3), 4.76(s, 2H, CH2), 7.13(d, J=7.8 Hz, 2H, ArH), 7.47(br s, 1H, NH), 7.68(d, J=7.8 Hz, 2H, ArH), 7.73(s, 1H, purine C8), 13.06(br s, 1H, COOH) | 169.50, 162.77, 157.79, 154.48, 150.83, 138.29, 129.74, 126.18, 114.50, 112.76, 55.62, 45.75, 45.61, 43.34, 43.21, 37.56, 30.54, 26.09, 25.47 |
Compd. | IC50 /(μmol·L-1) | Compd. | IC50 /(μmol·L-1) | ||||
---|---|---|---|---|---|---|---|
PC-3 | HCT116 | K562 | PC-3 | HCT116 | K562 | ||
13d | 23.4 | > 50 | > 100 | 17d | 19.1 | 27.3 | 33.1 |
13g | 39.7 | > 50 | > 100 | Roscovitine | 12.1 | 21.2 | 26.6 |
17c | > 50 | 26.7 | 47.6 |
Table 3 Cytotoxicity of representative compounds in vitro
Compd. | IC50 /(μmol·L-1) | Compd. | IC50 /(μmol·L-1) | ||||
---|---|---|---|---|---|---|---|
PC-3 | HCT116 | K562 | PC-3 | HCT116 | K562 | ||
13d | 23.4 | > 50 | > 100 | 17d | 19.1 | 27.3 | 33.1 |
13g | 39.7 | > 50 | > 100 | Roscovitine | 12.1 | 21.2 | 26.6 |
17c | > 50 | 26.7 | 47.6 |
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